Expeditious metal-free access to functionalized polycyclic acetals under mild aqueous conditions

Article abstract of DOI:10.1021/ol501986f

A facile approach for the synthesis of furopyrans and bicyclic bisacetals under mild aqueous conditions is described. This potentially green, diversity oriented approach involves cascade Michael addition and cycloacetalization of pyranones and 1,3-dicarbo

Full text of DOI:10.1021/ol501986f

Letter
pubs.acs.org/OrgLett
Expeditious Metal-Free Access to Functionalized Polycyclic Acetals
under Mild Aqueous Conditions
Sanghratna Kasare, Siddheshwar K. Bankar, and S. S. V. Ramasastry*
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Sector 81, S. A. S. Nagar,
Manuali PO, Punjab 140306, India
S
* Supporting Information
ABSTRACT: A facile approach for the synthesis of furopyrans and bicyclic bisacetals under mild aqueous conditions is
described. This potentially green, diversity oriented approach involves cascade Michael addition and cycloacetalization of
pyranones and 1,3-dicarbonyls. An interesting switch in the product class was observed depending on the type of pyranone
employed. Products of type I and II obtained herein are an integral part of several bioactive natural products and medicinally
interesting compounds.
raditional medicinal chemistry leading to drug discovery
T
involves the study of complex biological processes by the
interaction of small drug-like molecules. Toward this, diversity
oriented synthesis (DOS), introduced by Schreiber, has emerged
as a powerful tool to rapidly populate skeletally complex and
stereochemically diverse small molecules.1 DOS pathways have
the potential to assemble privileged substructures which are an
essential part of complex molecules often employed in drug
discovery processes. For example, heteroannular acetals are part
of a diverse range of natural products and several pharmaceut-
icals.2 Among fused bicyclic acetals, tetrahydrofuro[2,3-b]pyrans
(or furopyrans) are an important subunit embodied in many
biologically significant compounds; notable examples include
striatins, striatals, erinacine J, pittosporatobiraside A, daphnodor-
ins, etc. (Figure 1).3 The presence of intricate structural features
coupled with biological activities have made these oxabicycles
interesting and challenging synthetic targets. Consequently, a
myriad of impressive approaches were developed to access
different types of heteroannular acetals.2,4 Although the existing
methods have contributed significantly to the development of
this area, these methods have several drawbacks, viz., poor
substrate scope often associated with low yields, difficult-to-
access starting materials, lack of atom and step economy, metal
mediated reactions, etc.
Figure 1. Some natural products and medicinally interesting
compounds under the purview of this methodology.
In order to optimize the reaction conditions that could lead to
the one-pot synthesis of furopyrans, in a previously unexplored
approach, reaction of the acetoxy pyranone 1a7 and acetylace-
tone 2a was chosen as the model to screen different base
mediated conditions. It was envisaged that, under basic
conditions, 1,3-dicarbonyls could potentially undergo Michael
addition followed by concomitant cycloacetalization8 via the
cyclization of enols and in situ generated oxonium ions.
Development of novel cascade processes has received great
attention owing to their ability to rapidly assemble complex
molecular architectures.5 Environmentally friendly variants of
such cascade reactions would further add to their significance.
Against this background and in continuation of expanding our
earlier studies6 on the chemistry of heteroaryl carbinols, we
initiated a program to develop a general methodology for the
development of a potentially green and diversity oriented
approach toward the synthesis of unprecedented heteroannular
acetals of general structures I and II (Figure 1).
Received: July 10, 2014
Published: July 30, 2014
© 2014 American Chemical Society
4284
dx.doi.org/10.1021/ol501986f | Org. Lett. 2014, 16, 4284−4287

Organic Letters
Letter
Accordingly, as shown in Table 1, various base and solvent
combinations were investigated. Initially when DBU was
carbonyloxy pyranones and 1,3-dicarbonyls (Table 2). Evidently,
complex di-, tri-, and tetracyclic and spirocyclic furopyranones
can be accessed via this methodology in a merely single step
maneuver. For example, reaction of pyranones 1a−1e with β-
a
Table 1. Investigation of the Reaction Parameters
a
Table 2. Scope of Various Pyranones and 1,3-Dicarbonyls
b
entry
1
base (2.2 equiv)
solvent
THF
time [h]
yield [%]
DBU
1
73
−
c
2
Et3N
THF
12
1
d
3
K2CO3
THF
75
54
50
55
62
70
88
73
78
78
80
64
−
4
5
6
7
Cs2CO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
−
THF
1
THF
3
MeOH
DMF
THF+water
water
brine
water
water
water
−
1
2
e
8
1
9
1
10
1
f
11
1
g
12
h
1
13
1
14
15
1
water
120
a
Reaction conditions: 1a (0.2 mmol), 2a (0.22 mmol), and base (0.44
mmol) in 1 mL of solvent were stirred at room temperature for an
b
appropriate time. Isolated yield after silica gel column chromatog-
c
d
raphy. Only Michael adduct was obtained. 1 equiv of 18-C-6 was
e
f
used. THF/water 2:3; 1 equiv of TBAI was used. In presence of 20
mol % sodium dodecyl sulfate (SDS). 1 equiv of SDS was added. In
g
h
presence of 20 mol % Triton X-100.
employed as a base in tetrahydrofuran solvent, gratifyingly
indeed, the bicyclic acetal 3a was isolated in 73% yield (Table 1,
entry 1). The structure of 3a (including the expected cis ring
fusion with an unusually high J value of 8.8 Hz) was deduced in
conjunction with the spectral data and was further confirmed
unambiguously by the single crystal X-ray diffraction analysis
(see Supporting Information (SI)).9 Encouraged by this result,
we set out to optimize reaction parameters for the conversion of
acetate 1a to the bicyclic acetal 3a. Reaction in the presence of
organic bases such as triethylamine (and pyridine) resulted in the
formation of only the Michael addition product (Table 1, entry
2). Subsequent Brønsted base screening led to the identification
of eco-friendly, cheap, and readily available sodium bicarbonate
suitable for the conversion of 1a to 3a (Table 1, entries 3−8). We
were especially delighted when substantial improvement in the
yield was observed with sodium bicarbonate in water as the
medium (Table 1, entry 9). Further efforts to improve the yield
were not successful. For example, conducting the reaction in
brine or the presence of surfactants (Table 1, entries 10−13)
could not improve the yield. Solvent-free conditions were found
to be encouraging but not appealing due to the moderate yield
(Table 1, entry 14). As expected, no product formation was
observed in the absence of a base (Table 1, entry 15).
Thus, we have identified via this comprehensive screening that
2 equiv of sodium bicarbonate under aqueous conditions at room
temperature are most suitable conditions for obtaining polycyclic
acetals from acetyloxy pyranones. It is worth mentioning that
biomass derived starting materials and “Green” reaction
conditions represent a truly sustainable method.
a
b
Having obtained the optimized conditions, we further
examined the scope of the reaction initially with a variety of
Reaction conditions: As described in Table 1. In the presence of 1
c
equiv of SDS. Yield based on starting material recovery.
4285
dx.doi.org/10.1021/ol501986f | Org. Lett. 2014, 16, 4284−4287

Organic Letters
Letter
diketones and β-keto(thio)esters generated bicyclic furopyr-
anones in good to excellent yields (Table 2, entries 1−7).
Interestingly, reaction with ethyl dioxovalerate 2e (Table 2, entry
5) furnished a 3:1 mixture of 3e and 3e′, originating from the two
possible enol tautomers. As expected, the major product
originated from the major tautomer. Pyranones 1c and 1d
having a quaternary carbon furnished conveniently the bicyclic
furopyranones in good yields (Table 2, entries 6 and 7)
indicating that 1,3-spacial interactions virtually have no role in
the formation of products. Functionalized tricyclic furopyr-
anones including those containing up to two quaternary carbons
can be conveniently accessed in very good yields when cyclic β-
dicarbonyls are employed (Table 2, entries 8−13). The
significance of this method is further established when natural
product-like tetracyclic furopyrans including tetracyclic spiro-
cycles are generated (Table 2, entries 14−18). For example, the
reaction of diketone 1e and acetate 2f furnished tetracyclic
spirofuropyranone 3o in very good yield (Table 2, entry 16).
Upon reaction, rather hydrophobic hydroxycoumarin 2h with
acetates 1a and 1c resulted in the formation of complex
tetracyclic furopyranones 3p and 3q, respectively, in moderate
yields (Table 2, entries 17 and 18).
Table 3. Scope of Various Alkoxy/Aryloxy Pyranones and 1,3-
Dicarbonyls
a
Apart from the acetates of pyranones as reactants, respective
benzoates were also subjected under optimized conditions,
however, yielding inconsistent results. While the reaction of
benzoate 1b with diketone 2a generated the furopyranone 3a in
90% yield (Table 2, entry 1) [88% with acetate 1a (Table 1, entry
9)], the reaction of benzoate 1b with diketone 2f furnished the
tricyclic furopyranone 3h only in 52% yield (Table 2, entry 9)
[81% with acetate 1a (Table 1, entry 8)]. Lower yields are
attributed to the hydrophobicity of pyranones rendered
especially by the benzoate moiety. Thus, due to their consistency
as well as ease of synthesis and handling, acetates of pyranones
were preferred over benzoates in this study.
a
Reaction conditions: As described in Table 1.
To gain mechanistic insight, chiral acetates 1f and 1g were
analysis of the spectral data. The formation of a sensitive yet
stable product possessing unusual bridgehead hemiketal and
acetal functionalities points to the apparent nonformation of an
oxonium ion (unlike the carbonyloxy pyranones) and eventual
cyclization of the enol onto ketone leading to the formation of
the hemiketal 5a. Very pleasingly, this reaction was found to be
quite general and a variety of functionalized bi-, tri-, and
tetracyclic bisacetals can be obtained with the proper choice of
pyran acetals and 1,3-dicarbonyls (5b−5k) (Table 3, entries 2−
11). The molecular structure of a representative example (5d)
was unambiguously confirmed by single crystal X-ray diffraction
analysis (see SI for details).9 The 2,7-dioxabicyclo[3.3.1]nonane
core thus accessed via this methodology is the substructure
embodied by the durumhemiketalolide family of natural
products.3
To further illustrate the generality and synthetic utility of this
methodology, furopyranone 3h was converted to the acetate 6
via chemo- and regioselective borohydride reduction followed by
acylation of resultant alcohol (Scheme 2).10 Hydrogenolysis of
the enone 6 generated the ketoacetate 7,12 which comprises the
carbon framework of bioactive natural products such as striatals,
pittosporatobiraside, etc. and is an advanced intermediate to the
synthesis of several medicinally important compounds.3 On the
other hand, pyranone 3h was converted to the phenol 8 via
copper(II) chloride mediated oxidative aromatization (Scheme
2).10,13 Phenol 8 possesses the core structure present in flavonoid
natural products such as daphnodorins and erysenegalensein J.3
In conclusion, we have introduced a practical and scalable
method for the formation of unprecedented tetrahydrofuro[2,3-
synthesized (Scheme 1).10 Reaction of (R)-1f with ethyl
Scheme 1. Efforts To Gain Insight about the Reaction
acetoacetate 2b (Scheme 1, eq 1) generated furopyranone 3b
as a completely racemic mixture indicating that the acetalization
step clearly proceeds via a preformed oxonium ion intermediate
(SN1 pathway) and the possibility of an SN2 pathway can be ruled
out.11 On the other hand, the reaction of (2R,6S)-1g obtained in
33:1 dr generated furopyranone 3r in 25:1 dr (Scheme 1, eq 2)
indicating that the SN1 pathway prevails. Further, the existence of
an oxidopyrylium intermediate can be ruled out under the (mild)
reaction conditions.
At this stage, we were curious about the fate of alkoxy and
aryloxy pyranones under the optimized conditions. Accordingly,
pyranones 4a−4e were prepared as per literature methods.10
Reaction of the tert-butoxy pyranone 4a with the diketone 2a,
surprisingly, generated the bicyclic bisacetal 5a in very good yield
(Table 3, entry 1), whose structure was deduced from careful
4286
dx.doi.org/10.1021/ol501986f | Org. Lett. 2014, 16, 4284−4287

Organic Letters
Letter
T. Tetrahedron 2006, 62, 8463. For durumhemiketalolide A, see:
(d) Cheng, S.-Y.; Wen, Z.-H.; Wang, S.-K.; Chiou, S.-F.; Hsu, C.-H.; Dai,
C.-F.; Chiang, M. Y.; Duh, C.-Y. J. Nat. Prod. 2009, 72, 152. For
pittosporatobiraside A, see: (e) Munesada, K.; Ogihara, K.; Suga, K.
Phytochem 1991, 30, 4158. For daphnodorins, see: (f) Taniguchi, M.;
Baba, K. Phytochem. 1996, 42, 1447. For erysenegalensein J, see:
(g) Wandji, J.; Awanchiri, S. S.; Fomum, Z. T.; Tillequin, F.; Michel-
Daniw, S. Phytochem. 1995, 38, 1309. (h) Ghosh, A. K.; Parham, G. L.;
Martyr, C. D.; Nyalapatla, P. R.; Osswald, H. L.; Agniswamy, J.; Wang,
Y.-F.; Amano, M.; Weber, I. T.; Mitsuya, H. J. Med. Chem. 2013, 56,
6792. (i) Rhode, O.; Hoffmann, H. M. R. Tetrahedron 2000, 56, 6479.
(4) Some selected references: (a) Ren, J.; Liu, Y.; Song, L.; Tong, R.
Org. Lett. 2014, 16, 2986. (b) Ma, X.; Tang, Q.; Ke, J.; Yang, X.; Zhang,
J.; Shao, H. Org. Lett. 2013, 15, 5170. (c) Muller, P.; Chappellet, S. Helv.
Chim. Acta 2005, 88, 1010. (d) Roggenbuck, P.; Schmidt, A.; Eilbracht,
P. Org. Lett. 2002, 4, 289. (e) Harris, J. M.; O’Doherty, G. A. Org. Lett.
2000, 2, 2983. (f) Roy, S. C.; Mandal, P. K. Tetrahedron 1996, 52, 12495.
(5) (a) Patil, N. T.; Shinde, V. S.; Gajula, B. Org. Biomol. Chem. 2012,
10, 211. (b) Lu, L.-Q.; Chen, J.-R.; Xiao, W.-J. Acc. Chem. Res. 2012, 45,
1278.
Scheme 2. Elaborations to Part Structures of Natural Products
b]pyranones and 2,7-dioxabicyclo[3.3.1]nonenones. In this
diversity oriented approach, polycyclic furopyranones can be
synthesized starting from readily and easily accessible 1,3-
dicarbonyls and acetoxy and benzoyloxy pyranones via the
Michael addition−cycloacetalization cascade under green
conditions. On the other hand, under the same conditions,
alkoxy and aryloxy pyranones and 1,3-dicarbonyls generate a
variety of bi-, tri-, and tetracyclic bisacetals. Further investigations
regarding the scope of this reaction with different nucleophiles
and elaboration of these methods to the total synthesis of
bioactive natural products are in progress.
(6) (a) Satpathi, B.; Dhiman, S.; Ramasastry, S. S. V. Eur. J. Org. Chem.
2014, 2022. (b) Dhiman, S.; Ramasastry, S. S. V. J. Org. Chem. 2013, 78,
10427. (c) Dhiman, S.; Ramasastry, S. S. V. Org. Biomol. Chem. 2013, 11,
4299. (d) Dhiman, S.; Ramasastry, S. S. V. Org. Biomol. Chem. 2013, 11,
8030. (e) Dhiman, S.; Ramasastry, S. S. V. Indian J. Chem. 2013, 52A,
1103.
(7) Achmatowicz, O., Jr.; Bukowski, P.; Szechner, B.; Zwierzchowska,
Z.; Zamojski, A. Tetrahedron 1971, 27, 1973.
(8) (a) For an isolated example undergoing Michael/cyclo-
acetalization was reported, see: Khalilova, Y. A.; Spirikhin, L. V.;
Salikhov, Sh. M.; Valeev, F. A. Russ. J. Org. Chem. 2014, 50, 117. (b) For
a similar yet different reaction, see: Knol, J.; Jansen, J. F. G. A.; van
Bolhuis, F.; Feringa, B. L. Tetrahedron Lett. 1991, 32, 7465.
(9) The crystal structures have been deposited at the Cambridge
Crystallographic Data Centre, and the deposition numbers CCDC
1002232 (for 3a) and CCDC 1007211 (for 5d) have been assigned.
(10) See Supporting Information for more details.
(11) Perhaps the reaction proceeds via an initial nondiastereoselective
Michael addition followed by an SN1 pathway.
(12) The relative stereochemistries in 6 and 7 were assigned in analogy
with literature reports; see: Ghosh, A. K.; Chapsal, B. D.; Baldridge, A.;
Steffey, M. P.; Walters, D. E.; Koh, Y.; Amano, M.; Mitsuya, H. J. Med.
Chem. 2011, 54, 622 and ref 3h.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectral data, and copies of 1H and 13C
NMR spectra of all new compounds including crystallographic
data (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ramsastry@iisermohali.ac.in.
Notes
The authors declare no competing financial interest.
(13) Kraus, G. A.; Johnston, B. E.; Applegate, J. M. J. Org. Chem. 1991,
56, 5688.
ACKNOWLEDGMENTS
■
With utmost respect and admiration, this research work is
dedicated to the memory of Prof. Carlos F. Barbas, III (The
Scripps Research Institute, La Jolla, CA, USA). We are grateful to
the DST, Govt. of India for financial support through Fast Track
Scheme (SR/FT/CS-156/2011). We thank IISER Mohali for
funding and for the NMR, mass, and X-ray facilities. We are
grateful to Prof. P. V. Bharatam (NIPER Mohali) and Prof. K. R.
Prasad (IISc, Bangalore) for helpful discussions. S.K. and S.K.B.
thank IISER Mohali for research fellowships.
REFERENCES
■
(1) (a) Burke, M. D.; Berger, E. M.; Schreiber, S. L. J. Am. Chem. Soc.
2004, 126, 14095. (b) Schreiber, S. L. Science 2000, 287, 1964.
(2) (a) Milroy, L.-G.; Zinzalla, G.; Loiseau, F.; Qian, Z.; Prencipe, G.;
Pepper, C.; Fegan, C.; Ley, S. V. ChemMedChem. 2008, 3, 1922.
(b) Milroy, L.-G.; Zinzalla, G.; Prencipe, G.; Michel, P.; Ley, S. V.;
Gunaratnam, M.; Beltran, M.; Neidle, S. Angew. Chem., Int. Ed. 2007, 46,
2493 and references cited therein. (c) List, B.; Shabat, D.; Barbas, C. F.,
III; Lerner, R. A. Chem.Eur. J. 1998, 4, 881.
(3) For striatins, see: (a) Hecht, H.-J.; Hofle, G.; Steglich, W.; Anke, T.;
Oberwinkler, F. J. Chem. Soc., Chem. Commun. 1978, 665. For striatals,
see: (b) Anke, T.; Oberwinkler, F. J. Antibiot. 1977, 30, 221. For
erinacine J, see: (c) Kawagishi, H.; Masui, A.; Tokuyama, S.; Nakamura,
4287
dx.doi.org/10.1021/ol501986f | Org. Lett. 2014, 16, 4284−4287